Safety Assessment of Phytochemicals Derived from the Globalized South African Rooibos Tea ( Aspalathus linearis) through Interaction with CYP, PXR, and P-gp

Rooibos tea ( Aspalathus linearis) is a well-known South African herbal tea enjoyed worldwide. Limited reports indicate the potential of rooibos tea to alter the activity of certain Cytochrome P450 (CYP450) isozymes. In this study, the phytochemical investigation of MeOH extract of A. linearis (leaves and stems) resulted in the isolation and characterization of 11 phenolic compounds. The MeOH extract exhibited significant inhibition of the major human CYP450 isozymes (CYP3A4, CYP1A2, CYP2D6, CYP2C9, and CYP2C19). The strongest inhibition was observed by the extract for CYP3A4 (IC₅₀ 1.7 ± 0.1 μg/mL) followed by CYP2C19 (IC₅₀ 4.0 ± 0.3 μg/mL). Among the tested phytochemicals, the most potent inhibitors were isovitexin on CYP3A4 (IC₅₀ 3.4 ± 0.2 μM), vitexin on CYP2C9 (IC₅₀ 8.0 ± 0.2 μM), and thermopsoside on CYP2C19 (IC₅₀ 9.5 ± 0.2 μM). The two major, structurally related compounds aspalathin and nothofagin exhibited a moderate pregnane-X receptor (PXR) activation, which was associated with increased mRNA expression of CYP3A4 and CYP1A2, respectively. These results indicate that a high intake of nutraceuticals containing rooibos extracts may pose a risk of herb-drug interactions when consumed concomitantly with clinical drugs that are substrates of CYP Enzymes.